engleski

Phenotype of Renal Tubular Cell Death During Delayed Graft Function

Background: Delayed graft function (DGF) independently predicts reduced 5 yr kidney transplant survival. Treatments of DGF are lacking. Cold ischemia (CI) is a significant risk factor for DGF but the mechanism by which CI leads to DGF is unknown. The aim of this study was to determine the effects of CI on donor kidneys alone versus CI followed by warm reperfusion after kidney transplant (CI+Txp). We hypothesized that CI alone would produce a different injury phenotype to CI+Txp. Methods: Male C57BL6 mice aged 8-12 weeks, were subjected to mouse kidney transplant. Donor kidneys were subjected to 3 hours CI in UW solution, and processed immediately or subjected to syngeneic mouse kidney transplant. Renal function was assessed by serum creatinine (SCr). Renal tubular cell (RTC) apoptosis and necrosis were quantified by an independent nephropathologist. TLR4, RIP3, cleaved BID, Bax, cleaved caspase-8 (CC8) and cleaved caspase-3 (CC3) were examined by immunoblot. Results: CI+ Txp resulted in a significantly increased SCr (1.9±0.15) vs. transplant without CI (0.3± 0.05). CI alone results in increased RTC apoptosis and CC3 but did not result in necrosis. In contrast, CI +Txp led to ; (1) increased CC8, cleaved BID, Bax and CC3, and thus increased RTC apoptosis and also increased programmed necrosis ; (2) increased RTC necrosis that was associated with increased RIP3 and TLR4.Conclusions: CI results in RTC apoptosis alone without necrosis. In contrast CI +Txp results in a distinct injury phenotype of RTC apoptosis, and also programmed necrosis that is associated with: (1) increased RIP3 and TLR4 ; (2) CC8 activation of BID, which may further promote bax activation and thus programmed necrosis. Understanding the phenotype of injury following prolonged CI and kidney transplant may lead to novel therapies for DGF.

Renal tubular cell death; delayed graft function

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